Project Summary/Abstract Hypertension is the leading risk factor for stroke, myocardial infarction, and chronic kidney disease. The prevalence of hypertension increases with age from less than 10% among adults aged 18-39 to more than 65% among adults above the age of 60. While there is a demonstrated benefit of blood pressure reduction on measures of hypertension-related morbidity and mortality, less than one half of elderly patients with hypertension achieve therapeutic control of blood pressure. Importantly, the mechanisms underlying age- related hypertension have not been fully elucidated. This proposal seeks to delineate the integrated renal and sympathetic nervous system mechanisms that regulate sodium balance and blood pressure in aging, with the goal of identifying potential therapeutic avenues and informing the personalized application of current antihypertensive therapies in the elderly. We hypothesize that an age-related reduction in afferent renal nerve activity contributes to sympathoexcitation, leading to sodium chloride cotransporter-mediated sodium retention and the development of age-related hypertension. We will use a novel method to selectively ablate the afferent renal nerves and test the age-dependent role of the afferent renal nerve-mediated mechanosensitive sympathoinhibitory reno-renal reflex in homeostatic responses to acute and chronic challenges to sodium and fluid balance. In Specific Aim 1, we will establish an age-dependent decrease in afferent renal nerve activity and a failure to increase afferent renal nerve activity in response to a chronic high salt diet. We will demonstrate that intact afferent renal nerve activity facilitates sympathoinhibition, sodium homeostasis, and normotension in response to an acute volume expansion that directly activates renal mechanoceptors in young Sprague-Dawley rats, and that the role of the afferent renal nerves in these responses is age-dependent. In Specific Aim 2, we will demonstrate that intact afferent renal nerve activity facilitates sympathoinhibition, sodium homeostasis, and normotension in response to chronic dietary high salt intake in young Sprague- Dawley rats. We will demonstrate that the role of the afferent renal nerves in these responses is age dependent, and that decreased afferent renal nerve responsiveness evokes age-dependent sodium retention and hypertension via an efferent renal nerve-mediated ?1-adrenoceptor-dependent pathway that activates the sodium chloride cotransporter. We will use bilateral renal denervation to demonstrate that removal of both the afferent and efferent renal nerves attenuates age-related sodium retention and hypertension, providing mechanistic insight that may inform candidate selection for ongoing human renal nerve ablation studies. Our studies will identify new therapeutic targets and inform current treatment paradigms for hypertension in the elderly, meeting an urgent public health need for the rapidly aging global population.